The major objective of this research program is to gain new insights into the molecular and cell biological mechanisms underlying the production and actions of insulin and related peptide hormones of the islets of Langerhans and the neuroendocrine system, including their genetic basis, evolutionary origins, and disorders in these processes, which may contribute to the pathophysiology of diabetes and/or other diseases. New projects and extensions of previous work are proposed as follows: (1) New studies on mice with gene disruptions of the neuroendocrine prohormone convertases, including PC5/6 isoform A, to assess its role in processing important hormonal and neuropeptide precursors in brain, hypothalamus, islets and gastrointestinal tract and including, studies on the processing of ghrelin and related CNS/hypothalamic peptides involved in regulation of food intake and energy metabolism, (2) New studies on the role of prohormone structure in cleavage site selectivity of individual neuroendocrine PC family members, (3) Studies on the fate of PC1/3 and PC2 in vivo in neuroendocrine cells after completion of processing of secretory granule contents, i.e., retention, secretion and/or degradation, (4) Further studies on the evolution of the insulin family of hormones and the detailed structural basis of insulin's interaction with and activation of the insulin receptor. These studies should all contribute to improving our understanding of the genetic, cellular and molecular biological, and evolutionary mechanisms underlying islet hormone production and action and should contribute to a better understanding of the pathophysiology of diabetes.